Abstract

The ability to expand memory T cells with cytokines ex vivo has greatly increased the practicality of adoptive immunotherapy for cancer. Central memory T cells generated in IL-15 have the advantage of longevity after subsequent in vivo transfer, whereas effector cells have the advantage of more immediate tumor cell killing. Here we report that in adoptive immunotherapy against a pre-established EG.7 tumor, a greater proportion of tumor bearing animals were cured with reactivated memory T cells as compared to animals that received central memory cells. Although central memory cells showed an initial survival advantage in the host, reactivated memory cells expanded more rapidly in the tumor, draining lymph node and spleen, resulting in increased accumulation over time. Co-administration of reactivated memory T cells with anti-4-1BB agonist antibody further potentiated the therapeutic effect. Anti-4-1BB therapy resulted in expansion of host NK, NKT, CD11c+ cells, CD4 and CD8 T cells as well as the adoptively transferred T cells. However, use of 4-1BB-deficient hosts showed that the expression of 4-1BB on adoptively transferred T cells was sufficient for the therapeutic effect. Thus, the combination of reactivated memory T cells and stimulatory anti-41BB antibody represents a superior immunotherapy for a rapidly growing cancer, largely through effects of anti-4-1BB on transferred effector T cells.